Education/Training Program Affiliations

Biomedical Science Program

Center, Program and Institute Affiliations

Center for Immunology and Immune-based Diseases

Research Summary

Staphylococcus aureus is the leading cause of serious infectious diseases, resulting in more fatalities in the U.S. than even AIDS. Contributing to these infections are both healthcare and community-associated, methicillin-susceptible and resistant S. aureus, corresponding largely to the USA100 to USA400 clonal types. We study diseases caused by strains of all four major clonal groups in highly sensitive rabbit models of infective endocarditis, sepsis, and pneumonia. A promising area of research for understanding and combatting S. aureus infections is the study of staphylococcal enterotoxins (SEs) also known as superantigens (SAgs). SAgs are major secreted virulence factors of S. aureus. It has been known for decades that these molecules cause vomiting and diarrhea (hence the name enterotoxin) but are also highly lethal in humans. Almost every S. aureus strain encodes for and can produce SAgs when the opportunity arises. It has become evident over the past years that SAgs are critical contributors to the pathophysiology of the life-threatening illnesses that S. aureus causes, including septicemia, endocarditis (which leads to fulminant heart infections), necrotizing and hemorrhagic pneumonias (including secondary bacterial pneumonia), and chronic skin infections (including diabetic foot ulcers). Most of these illnesses carry high mortality rates, even with current available treatments.

Superantigen Mechanism in Infective Endocarditis

Infective endocarditis, which occurs in 30-60% of patients with S. aureus bacteremia, is an infection of the heart endothelium, predominantly valves, that results in the formation of large vegetative lesions composed of host factors and bacterial aggregates. Vegetations often lead to congestive heart failure and systemic embolization, resulting in strokes, metastatic abscesses, persistent bacteremia, and toxic shock syndrome (TSS). Over the past decades, infective endocarditis outcomes have not improved (mortality rates are still 40-50%), and infection rates are steadily increasing. We have shown that highly produced SAgs (as TSST-1 and SEC) are critical for vegetation formation. We are currently defining the underlying mechanism of superantigen involvement.

Superantigen Enhancement of Endotoxin Shock

Endotoxemia occurs in humans during TSS and in rabbits injected with TSST-1. An interesting and potentially important property of SAgs is their ability to enhance the lethality of lipopolysaccharide (LPS) by up to a million fold. Furthermore, the susceptibility of humans and rabbits to SAgs correlates with the presence of gram-negative rods bearing toxic LPS colonizing the intestinal and vaginal tracts. Superantigen-induced LPS enhancement results from impaired LPS clearance by the liver. We are elucidating the mechanism of LPS and superantigen synergism in in vitro and in vivo systems.